Rejection and infective complications resulting from immunosuppressive treatment are the principal causes of failure of organ allografting in man, that is, an organ graft made between two genetically different individuals in the same Homo sapiens species. In order to minimize the individual specific side-effects of the three effective agents used in clinical practice, namely azathioprine, corticosteroids and cyclosporin, small doses of each are used in combination "triple therapy". Of the three agents currently used in such triple therapy, cyclosporin is the most powerful, but has the unsatisfactory side-effect of nephrotoxicity in man which can lead to structural renal damage. Increased corticosteroid dosage and antilymphocyte antibody preparations, poly- or monoclonal, are used for the treatment of rejection crises. A number of studies have been taken to investigate other potentially effective compounds for use as immunosuppressants and transplant rejection inhibitors, but to date, none have been found to be useful in clinical settings because of side-effects, such as toxicity, the lack of efficacy or a combination of these factors.
The fungal product FK506 was reported to have immunosuppressive activity in animals with organ grafts (Ochiai, T., et al., Transplant. Proc., Vol. XX, No. 1, pp. 209-214, 1988). Although the immunosuppressive activity of FK506 was confirmed, the toxicity in mammals, such as rats, pigs and dogs, and in primates, e.g., baboons, was too severe to proceed to clinical phase trials (Collier, D. St. J., et al., Transplant. Proc., Vol. XX, No. 1, pp. 226-228, 1988).
It would be extremely useful to discover a compound having immunosuppressive activity which could be employed to increase transplant acceptance in a recipient but without causing serious toxic side effects typically associated with conventional immunosuppressant therapy, such as those discussed above.
Rapamycin is a lipophilic macrolide with certain structural similarities to FK506 produced by Strectomyces hyoroscopicus with both antifungal and antitumor properties (Sehgal, S. N. et al., J. Antibiot., Vol. 28, pp. 727-732, 1975; Eng. C. P., et al., J. Antibiot., Vol. 37, pp. 1231-1237, 1984).
It was reported that rapamycin inhibited two experimental immunopathies, i.e., experimental allergic encephalitis and adjuvant arthritis, and the formation of humoral (IgE-like) antibody. (Martel, R. R., et al., Can. J. Physio. Pharmacol., 55: 48-51, 1977) It has also been reported recently that rapamycin inhibits murine T cell activation, apparently through a different mechanism from FK506. (Staruch, M. J., et al., The FASEB Journal, Vol 3, No. 3, abstract #3411, 1989). In addition, it was disclosed that rapamycin blocks the immunosuppressive effect of FK506 but not that of cyclosporin A (Dumont, F. J. et al., The FASEB Journal, Vol. 3, No. 4, abstract #5256, 1989). There was no teaching or suggestion in these reports, however, that rapamycin could or should be used to effectively inhibit organ or tissue transplant rejection in mammals. Furthermore, these reports do not disclose or intimate that the toxic side-effects associated with FK506, and other immunosuppressive agents, would not likewise arise from administering rapamycin as an agent to inhibit transplant rejection in transplant operations.